Intranasal delivery of apelin-13 is neuroprotective and promotes angiogenesis after ischemic stroke in mice

• Type of Material: Article
• Authors: Dongdong Chen, Emory University; Jinhwan Lee, Emory University; Xiaohuan Gu, Emory University; Ling Wei, Emory University; Shan Yu, Emory University
• Language: English
• Date: 2015-01-01
• Publisher: SAGE Publications (UK and US): Creative Commons Attribution
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2015
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1177/1759091415605114
• Title of Journal or Parent Work: ASN NEURO
• ISSN: 1759-0914
• Volume: 7
• Issue: 5
• Grant/Funding Information: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by an AHA Grant-in-Aid Grant 12GRNT12060222 (SPY), NS062097 (LW), NS075338 (LW), NS085568 (LW/SPY), and a VA Merit Grant RX000666 (SPY).
• Keywords: inflammation; apelin-13; functional recovery; ischemic stroke; angiogenesis; neuroprotection
• Research Categories: Health Sciences, General; Biology, Neuroscience

Abstract

© The Author(s) 2015. Apelin is a peptide originally isolated from bovine stomach tissue extracts and identified as an endogenous ligand of the APJ receptor; recent work showed that apelin ameliorates the ischemic injury in the heart and the brain. Being an analogue to the angiotensin II receptor, the apelin/APJ signaling may mediate angiogenesis process. We explored the noninvasive intranasal brain delivery method and investigated therapeutic effects of apelin-13 in a focal ischemic stroke model of mice. Intranasal administration of apelin-13 (4 mg/kg) was given 30 min after the onset of stroke and repeated once daily. Three days after stroke, mice received apelin-13 had significantly reduced infarct volume and less neuronal death in the penumbra. Western blot analyses showed upregulated levels of apelin, apelin receptor APLNR, and Bcl-2 and decreased caspase-3 activation in the apelin-13-treated brain. The proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1β, and chemokine monocyte chemoattractant protein-1 mRNA increased in the ischemic brain, which were significantly attenuated by apelin-13. Apelin-13 remarkably reduced microglia recruitment and activation in the penumbra according to morphological features of Iba-1-positive cells 3 days after ischemia. Apelin-13 significantly increased the expression of angiogenic factor vascular endothelial growth factor and matrix metalloproteinase-9 14 days after stroke. Angiogenesis illustrated by collagen IV+/5-bromo-20-deoxyuridin+colabeled cells was significantly increased by the apelin-13 treatment 21 days after stroke. Finally, apelin-13 promoted the local cerebral blood flow restoration and long-term functional recovery. This study demonstrates a noninvasive intranasal delivery of apelin-13 after stroke, suggesting that the reduced inflammatory activities, decreased cell death, and increased angiogenesis contribute to the therapeutic benefits of apelin-13.